The present invention relates to an improved process for the manufacturing of an alkaline salt of an acid susceptible proton pump inhibitor compound, such as a substituted sulphinyl heterocyclic compound containing an imidazole moiety. More specifically the invention is related to an improved process for the manufacturing of an alkaline salt of omeprazole or an alkaline salt of (S)-omeprazole, preferably magnesium salts of these compounds. The invention is also related to an improvement in the preparation of the pharmaceutical formulation and to products containing as the active ingredient a compound prepared by the claimed processes as well as the use of the products in medicine.
Substituted benzimidazoles such as for instance the compounds with the generic names omeprazole, lansoprazole, pantoprazole, rabeprazole and leminoprazole have properties making the compounds useful as inhibitors of gastric acid secretion. This class of compounds is known as proton pump inhibitors or H+,K+-ATPase inhibitors. There are a large number of patents and patent applications disclosing such proton pump inhibitors and processes for their manufacturing.
There is a general need in industry that pharmaceutically active compounds should be produced by processes giving products with properties, such as being easy to handle in full scale manufacturing and having good stability during storage, making them suitable for pharmaceutical preparations. The active substance, the drug, should also be presented in a form with such physico-chemical properties that are suitable for pharmaceutical manufacturing processing, and the drug should be released from the dosage form with a rate suitable for its intended pharmacological effect. Usually, it is the concern of the formulator to develop dosage forms with the desired properties. However, to obtain a good formulation, it is beneficial and important that the active substance as such is prepared and presented in the most suitable form.
WO 95/01977 discloses a magnesium salt of omeprazole with a specific degree of crystallinity making the claimed product especially suitable for pharmaceutical formulations; this is also discussed in WO 95/01783.
An efficient process for the manufacture of a magnesium salt of omeprazole is described in WO 97/41114. This process comprises mixing and reacting omeprazole with a weak base and a magnesium source and optionally the reaction takes place in the presence of an organic solvent. After the reaction is completed, the product is preferably crystallised from the filtrate.
Other processes related to the manufacture of alkaline salts of proton pump inhibitors are for instance disclosed in WO 94/27988, in which the preparation of the single enantiomers of omeprazole and alkaline salts thereof is described.
The present invention provides improvements over the prior art processes. It represents especially an improvement of the process described in WO 97/41114.
A pharmaceutical dosage form suitable for proton pump inhibitor compounds is for instance described in WO 96/01624. Said patent application describes preparation of small enteric coating layered pellets comprising the active substance. These enteric coating layered pellets are compressed into tablets. Preferably, the preparation of pellets containing the active substance is performed by spray layering the active substance onto seeds, such as for instance sugar spheres, and thereafter applying the enteric coating layer, optionally after a separating layer has first been applied to separate the active substance from the finally applied enteric coating layer.
Proton pump inhibitor compounds are acid susceptible and with respect to the stability properties of these compounds, it is obvious that an oral solid dosage form must be protected from contact with the acidic gastric juice and that active drug must be transferred in intact form to that part of the gastrointestinal tract where pH is near neutral and where rapid absorption can occur.
The rate of release of the drug from a pharmaceutical dosage form can influence the total extent of absorption of such a drug into the general circulation. Omeprazole and related drugs as well as dosage forms comprising these drugs have been investigated (See for instance Pilbrant and Cederberg, Scand. J. Gastroenterology 1985; 20 (suppl. 108) p. 113-120). The marketing approval for these products specifies limits for the rate of release of the drug from the pharmaceutical dosage form.
The present invention provides an improved process for the preparation of an alkaline salt of a substituted sulphinyl heterocycle containing an imidazole moiety and especially magnesium salts of substituted benzimidazole derivatives. The process results in a bulk product, which on addition of water, gives a suspension with a pH above a specified pH range. Said product is suitable for further processing into a pharmaceutical preparation. The release properties of such a pharmaceutical formulation comprising the new form of the active substance are improved. The claimed process provides especially a more suitable bulk drug product for pharmaceutical dosage forms, for intance a multiple unit tablet.
According to the improved process, an alkaline salt of a substituted sulphinyl heterocycle containing an imidazole moiety is prepared, and the process comprises a final step wherein a base is added to a washing solvent to adjust the pH of the solution, which solution is used in the final wash of the product. Preferably, a magnesium salt of the substituted sulphinyl heterocycle compound is prepared according to WO 97/41114, hereby included by reference, by mixing and reacting the substituted sulfinyl heterocycle compound with a weak base, preferably an amine or ammonia, and a magnesium source, such as an organic or inorganic magnesium salt or a combination of such salts. Thereafter the crystallised and isolated magnesium salt product is washed with a basic aqueous solvent mixture.
The process may also be used to prepare other salts of substituted sulphinyl heterocycles containing an imidazole moiety, for instance slightly soluble or less soluble salts, preferably a multivalent salt such as a calcium salt, by the use of a calcium source or any other suitable source of that cation. Slightly soluble or less soluble salts are defined in compliance with the European Pharmacopiea (Edition 3) under the heading xe2x80x9cGeneral noticexe2x80x9d.
The present invention also provides an improved process for the preparation of a pharmaceutical dosage form by spray layering of the active substance onto seeds, such as for instance sugar spheres. The active substance is preferably an acid susceptible drug selected from an alkaline salt of a substituted sulphinyl heterocycle containing an imidazole moiety. The active substance is suspended in an aqueous solution of a macromolecular binding agent. The obtained suspension should have a pH not significantly lower than that of a saturated water solution of the pure drug substance.
In one preferred embodiment, the claimed process relates to a process for the manufacturing of dosage forms comprising magnesium salts of substituted benzimidazole derivatives. More specifically, the process is related to the preparation of spray layered spheres with omeprazole magnesium in a water solution of a binding agent. The prepared pellets are covered by a separating layer and an enteric coating layer and filled into a capsule, or mixed with tablet excipients and compressed into a tableted multiple unit dosage form. Preferably, a tablet comprising a multiple of enteric coating layered units of omeprazole magnesium is prepared.